Project Summary The transcription factor Aryl Hydrocarbon receptor (AhR) interacts with small molecules and modulates T helper (Th) cell differentiation and cytokine secretion. However, the AhR can interact with agonists, pure antagonists, or Selective AhR Modulators (SAhRMs), which have different effects on Th cell function. Chronic airway inflammatory diseases affect greater than 300 million people worldwide, with up to 11% of the population of the United States alone. Currently chronic airway inflammation can be controlled not cured, making them among the most expensive diseases for healthcare systems in developed countries. A hallmark of chronic airway inflammation is the increase in Th cytokines, Interleukins (IL) 4, 5, 13, or IL17A, IL17F and IL22 that affect inflammation in the lung and airways hyper responsiveness. Current therapies largely revolve around the use of corticosteroids for suppression of inflammation, which while effective, have significant side effects. More recent efforts targeting these cytokines in asthma using monoclonal antibodies are moving their way through the clinic, but one potentially powerful approach would be small molecule manipulation of the Th cytokine response during the inflammatory process. We suggest that such functional differences in AhR ligands may be exploited to manipulate T helper cytokines in airway inflammation, thus reducing it. The objective of this application is therefore to determine the mechanism by which AhR ligands, agonist, SAhRM and antagonist, act to modulate Th cell cytokine secretion and airway inflammation. We will test the hypothesis that different classes of Aryl hydrocarbon Receptor ligands differentially regulate AhR function to tune T helper cell differentiation and function, thereby modulating airway inflammation. Our specific aims are to: 1) determine the ability of AhR ligands and SAhRMs to modulate airway inflammation, and 2) determine the role of AhR ligands and SAhRMs in modulating T cell differentiation. This work is extremely innovative because we have an exciting hypothesis that different classes of AhR ligands are able to differentially regulate AhR function, and thus manipulate Th differentiation during airway inflammation. We have also proposed novel approaches to study the mechanism by which these selective AhR ligands alter Th differentiation. Furthermore, we have assembled a unique team, with deep expertise in analysis of the immunological basis for airway inflammation, and outstanding expertise in the study of the AhR and ligands such as SAhRMs. This combination brings incomparable synergy to the study of the AhR in Th cytokine responses. Our work therefore has immediate implications on approaches to treat chronic airway inflammatory diseases such as asthma and Hypersensitivity pneumonitis in humans, as manipulation of the T cell response with small molecule modulators of the AhR may be able to affect these diseases.